System for Brugada syndrome presence-based electrical therapeutic stimulation delivery

ABSTRACT

Brugada syndrome and related forms of ion channelopathies, including ventricular asynchrony of contraction, originate in the region near the His bundle or para-Hisian regions of the heart. Manifestations of Brugada syndrome can be corrected by delivering endocardial electrical stimulation coincident to the activation wave front propagated from the atrioventricular (AV) node. By performing the start of the activation of the HIS bundle or para-Hisian region early enough, electrical stimulation can be delivered fast enough to compensate for the conduction problems that start in those region, such that the activation wave front, as stimulated, transitions from the AV node to the His bundle in a normal, albeit electrically-supplemented, fashion. This stimulation not only helps resolve the conditions that trigger Brugada syndrome, but also resolves the asynchrony of the contraction of the heart.

CROSS-REFERENCE TO RELATED APPLICATION

This non-provisional patent application is a continuation of U.S. Pat.No. 11,033,744, issued Jun. 15, 2021; which is a continuation of U.S.Pat. No. 10,335,600, issued Jul. 2, 2019, the disclosures of which areincorporated by reference.

FIELD

This application relates in general to treatment of cardiac rhythmdisorders and, in particular, to a system for Brugada syndromepresence-based electrical therapeutic stimulation delivery.

BACKGROUND

Brugada syndrome is a distinct form of genetically-determined idiopathiccardiac arrhythmia syndrome that can lead to syncope, cardiac arrest andsudden cardiac death (SCD). The syndrome is a genetic form of cardiacrhythm disorder caused by an inherited ion channelopathy. Brugadasyndrome has been observed in the electrocardiograms of otherwisehealthy young individuals without evidence of structural heart diseasewho are of Southeast Asian descent. Men are eight to ten times morelikely to suffer Brugada syndrome. The syndrome has anautosomal-dominant pattern of transmission in about half of the familialcases observed and primarily affects Southeast Asian men, especiallyThai and Laotian, in the 30-50 year age range, with a median age of 41years.

The prognosis in Brugada syndrome is poor. Although the exact incidenceof SCD due to Brugada syndrome is unknown, the magnitude of the problemhas been estimated to range from 180,000 to 450,000 deaths annually inthe United States alone. Further, about 2.5% of all cardiac arrest casesin which the patient showed no clinically identifiable cardiacabnormalities have been attributed to Brugada syndrome. The syndromealso accounts for 4% to 12% of all SCDs in genetically pre-disposedindividuals, and a 40% mortality rate has been observed in symptomaticpatients at two to three years follow up, with a 2% to 4% mortality ratein asymptomatic patients. During electrophysiologic studies (EPS),asymptomatic patients with induced ventricular tachycardia (VT) orventricular fibrillation (VF) exhibited four times more SCD thannon-inducible patients.

The cause of death in Brugada syndrome is due to VF, yet the precisemechanism underlying the electrocardiographic changes observed insymptomatic patients having Brugada syndrome is unknown. Pathologically,in 20% of observed cases, the syndrome has been associated withmutations in SCN5A gene expression, located in chromosome 3, whichencodes for sodium ion channel transport to cell membranes of cardiacmyocytes. Loss-of-function mutations in this gene have been theorized tolead to a failure of the action potential dome to develop, that in turncauses persistent ST segment elevation. The clinical events observedcoincident to the electrocardiographic markers of Brugada syndrome, fromsyncope to VT to VF to SCD, are triggered by polymorphic ventriculararrhythmias, whose mechanism could be a Phase 2 reentry in the areaaround the right ventricular outflow tract.

Conventional approaches to treating Brugada syndrome focus on preventingor ameliorating VT and VF. For instance, implantable cardiac rhythmmanagement devices, particularly automatic implantablecardioverter-defibrillator (ICDs), and, to a lesser extent,transiently-introduced electrophysiology catheters, apply a therapybased on the reversion of already-established polymorphic arrhythmias,such as described in Lee et al., “Prevention of Ventricular Fibrillationby Pacing in a Man with Brugada Syndrome,” J. Cardiovasc.Electrophysiol., Vol. 11, pp. 935-937 (August 2000), the disclosure ofwhich is incorporated by reference. Similarly, Quinidine-basedpharmaceutical therapies have also been used to effectively prevent VFinduction and suppress spontaneous arrhythmias. Finally, surgicalinterventions through ablation at the right ventricular outflow tractlevel have been explored. Notwithstanding, these approaches constituteaggressive interventions and are impracticable to use on the largepopulation that is theorized to have the Brugada syndrome, as only asmall percentage will develop VT or VF, or experience cardiac arrest orSCD.

Therefore, a need remains for an approach to proactively treating theconduction and activation problems underlying the Brugada syndrome,rather than focusing on only avoiding or alleviating the deleterioussequelae of the syndrome.

SUMMARY

Brugada syndrome and related forms of ion channelopathies, includingventricular asynchrony of contraction, originate in the region near theHis bundle or para-Hisian regions of the heart. Manifestations ofBrugada syndrome can be corrected by delivering endocardial electricalstimulation coincident to the activation wave front propagated from theatrioventricular (AV) node.

In one embodiment, a system for Brugada syndrome presence-basedelectrical therapeutic delivery. The system includes a cardiac pacingdevice including a pulse generator and a pair of pacing electrodeselectrically coupled to the pulse generator via an endocardial lead andpositioned in one of a region near the His bundle and a para-Hisianregion of a patient's heart, the pulse generator configured to deliverelectrical therapeutic stimulation through the pair of pacing electrodessubstantially coincident to propagation of an activation wave frontproceeding from the atrioventricular node of the patient's heart; and adiagnostic module operatively coupled to the pulse generator andconfigured to sense via one or more sensing electrodes physiologyassociated with a presence of Brugada syndrome in the patient, thediagnostic module further configured to control the pulse generator indelivering the electrical therapeutic stimulation in response to thepresence of Brugada syndrome, wherein the physiology associated with thepresence of Brugada syndrome comprises a QRS duration in a lead V2longer than 90 msec and one of an inferolateral J wave and a horizontalST segment morphology following a J wave.

In a further embodiment, a cardiac rhythm management system for treatingBrugada syndrome is provided. The system includes an endocardial leadcomprising a pair of pacing electrodes and at least one sensingelectrode both on a distal end that has been positioned in one of aregion near the His bundle and a para-Hisian region of a patient'sheart; and a cardiac rhythm management device comprised in a sealedhousing and further including: a sensing amplifier electrically coupledto the endocardial lead and configured to detect through the at leastone sensing electrode propagation of an activation wave front proceedingfrom the atrioventricular node; a pulse generator electrically coupledto the endocardial lead and configured to deliver electrical therapeuticstimulation under programmed parametric control, the pulse generatorfurther configured to deliver the electrical therapeutic stimulationthrough the pair of pacing electrodes substantially coincident to theactivation wave front as detected by the sensing amplifier; and adiagnostic module operatively coupled to the pulse generator and thesensing amplifier and configured to sense via the at least one sensingelectrode physiology associated with a presence of Brugada syndrome inthe patient, the diagnostic module further configured to control thepulse generator in delivering the electrical therapeutic stimulation inresponse to the presence of Brugada syndrome, wherein the physiologyassociated with the presence of Brugada syndrome comprises a QRSduration in a lead V2 longer than 90 msec and one of an inferolateral Jwave and a horizontal ST segment morphology following a J wave.

In a still further embodiment, a catheter-based cardiac rhythmmanagement system for treating Brugada syndrome is provided. The systemincludes an electrophysiology catheter configured to betransiently-introduced into the heart of a patient and including aplurality of electrodes on a distal end; a sensing amplifierelectrically coupled to the electrophysiology catheter and configured todetect through the electrodes propagation of an activation wave frontproceeding from the atrioventricular node; and a pulse generatorelectrically coupled to the electrophysiology catheter and configured todeliver electrical therapeutic stimulation under programmed parametriccontrol through the electrodes via the electrophysiology catheter whendistally positioned in one of a region near the His bundle and apara-Hisian region of a patient's heart, the pulse generator furtherconfigured to deliver electrical therapeutic stimulation through theelectrodes substantially coincident to the activation wave front asdetected by the sensing amplifier; and a diagnostic module operativelycoupled to the pulse generator and the sensing amplifier and configuredto sense via at least one of the electrodes physiology indicative of apresence of Brugada syndrome in the patient, the diagnostic modulefurther configured to control the pulse generator in delivering theelectrical therapeutic stimulation in response to the presence ofBrugada syndrome, wherein the physiology associated with the presence ofBrugada syndrome comprises a QRS duration in a lead V2 longer than 90msec and one of an inferolateral J wave and a horizontal ST segmentmorphology following a J wave.

Still other embodiments will become readily apparent to those skilled inthe art from the following detailed description, wherein are describedembodiments by way of illustrating the best mode contemplated. As willbe realized, other and different embodiments are possible and theembodiments' several details are capable of modifications in variousobvious respects, all without departing from their spirit and the scope.Accordingly, the drawings and detailed description are to be regarded asillustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing placement of an implantablecardiac rhythm management device in a male patient for treating Brugadasyndrome, in accordance with one embodiment.

FIGS. 2 and 3 are graphs showing, by way of example, 12-leadelectrocardiograms for patients exhibiting Brugada syndrome.

FIG. 4 is a flow diagram showing a method for treating Brugada syndromethrough triggered pacing in accordance with one embodiment.

FIG. 5 is a flow diagram showing a method for treating Brugada syndromethrough optimized atrioventricular nodal pacing in accordance with afurther embodiment.

FIG. 6 is a flow diagram showing a method 100 for selecting an algorithmfor detecting Brugada syndrome for use in conjunction with the methodsof FIGS. 4 and 5 .

FIGS. 7A-B, 8A-B and 9A-B are graphs respectively showing, by way ofexample, 12-lead electrocardiograms for patients exhibiting Brugadasyndrome following treatment through the methods of FIGS. 4 and 5 .

FIG. 10 is a flow diagram showing a method 100 for sensing QRS width foruse in conjunction with the methods of FIGS. 4 and 5 .

FIG. 11 is a functional block diagram showing a computer-implementedsystem for treating Brugada syndrome, in accordance with a furtherembodiment.

DETAILED DESCRIPTION

Implantable cardiac rhythm management (CRM) devices include pacemakers,implantable cardioverter-defibrillators (ICDs), and cardiacresynchronization therapy (CRT) devices. CRM devices and, to a lesserextent, transiently-introduced electrophysiology catheters, such as usedto induce ventricular arrhythmias during electrophysiologic studies(EPS), currently provide the only effective means for treating thesequelae VT and VF triggered by the syndrome and thereby help to preventSCD. However, these devices focus on preventing or ameliorating VT andVF, rather than directly addressing the elimination of theelectrocardiographic pattern typical of Brugada syndrome and relatedforms of channelopathies and cardiac asynchrony disorders.

Conventional arrhythmia management using CRM devices is episode-focused.Changes in heart rhythm are monitored by a CRM device as arrhythmicepisodes potentially requiring therapy to convert, mitigate, orinterrupt the dysrhythmia. Pacemakers, for instance, manage bradycardia,which is an abnormally slow or irregular heartbeat, by delivering pacingstimuli to restore normal sinus rhythm through electrodes provided onendocardial pacing leads. Implantable cardioverter defibrillators (ICDs)treat tachycardia, which are abnormally fast and life threatening heartrhythms, through high energy cardioversion, defibrillation shocks, oranti-tachycardia pacing.

Brugada syndrome, as well as other forms of conduction problems thatstart in the His and para-Hisian regions, such as ventricular asynchronyof contraction, can be corrected by actively stimulating those regionsof the heart as the activation wave front coming from theatrioventricular (AV) node enters using an implantable CRM device. FIG.1 is a front anatomical diagram showing placement of an implantable CRMdevice 19 in a male patient 10 for treating Brugada syndrome, inaccordance with one embodiment. Depending upon type, CRM devices canprovide therapeutic electrical stimuli for up to three chambers of theheart. Single-chamber CRM devices rely on one endocardial lead attachedto either the right atrium or right ventricle, while dual-chamber CRMdevices utilize a pair of endocardial leads attached to the right atriumand right ventricle. Triple-chamber CRM devices use endocardial leads inthe right atrium and right ventricle and coronary venous leads in theleft ventricle.

The implantable CRM device 19 is preferably at least a dual-chamber CRMdevice that is surgically implanted subcutaneously in the patient'spectoral region or other suitable location in situ. A pair ofdual-chamber endocardial leads 19 are guided through the left subclavianvein (not shown) and superior vena cava 18 into the right atrium 12 andright ventricle 13 of the heart 11 for providing cardiac physiologicalmonitoring within and for delivering electrical therapy to the patient'sheart 11. For the sake of clarity, the endocardial leads 19 are shownleading directly into the heart 11, although different placement andorientation may be used during actual implantation. Other forms of CRMmay require placement of endocardial leads in the left atrium 14 or leftventricle 15 of the heart 11. For the sake of completeness, twoendocardial leads 21, 22 are shown, although only the endocardial lead21 and its pacing electrodes 23 that are distally located in the regionnear the His bundle 16 or para-Hisian region 17 are directly addressedin the delivery of pacing therapy for treating Brugada syndrome.

In the general sense, electrical stimuli can be delivered through pacingelectrodes 23, 25 respectively on the distal ends of each of theendocardial leads 21, 22, although only the pacing electrodes 23 thatare distally located in the region near the His bundle 16 or thepara-Hisian region 17 are of interest herein. By way of example, thepacing electrodes 23, 25 are bipolar electrodes, but the pacingelectrodes could also be unipolar or tripolar. In a further embodiment,the endocardial leads 21, 22 can also respectively include sensingelectrodes 24, 26 located near their distal ends for monitoringphysiology indicative of a presence of Brugada syndrome. In a stillfurther embodiment, the pacing electrodes 23, 25 could be alternativelyre-purposed to sense physiology between deliveries of electricalstimuli.

The implantable CRM device 19 also encloses operational circuitry withina hermetically-sealed housing 28, which generally includes controlcircuitry 27; inductive transducer 28; oscillator 29; wirelesstransceiver 30; memory 31; and power source 32, which provides a finitepower supply for the operational circuitry. The control circuitry 27implements the implantable CRM device's functionality and controls pulsegenerator output circuitry 33 for delivering electrical stimulationtherapy through the pacing electrodes 23, 25 to the heart 11, andsensing amplifiers 34 for monitoring cardiac physiology in the heart 11through the sensing electrodes 24, 26. The transducer 28 providesinductive signal conversion to enable remote parametric programming ofthe implantable CRM device 19 and stored physiologic data offload fromthe memory 31 through an external programmer or similarinductively-coupled device, as further described infra with reference toFIG. 11 . The oscillator 29 regulates internal CRM device operation bycontrolling timing. The wireless transceiver 30 enables wirelesscommunications with an external computer or similarwirelessly-interfaced device, as also further described infra withreference to FIG. 11 . Finally, the memory 31 stores monitored cardiacphysiology, such as the patient's monitored physiometry; environmentaldata, for instance, ambient temperature or time of day; and parametricinformation, including programming, status, and device operationalcharacteristics for the implantable CRM device 19 proper. The parametricinformation can include pacing parameters, including electrical stimuliwaveform, voltage, amplitude, phase, pulse width, rate, inter-pulsedelay, pacing duration, inter-pacing delay, and so forth. Still otherkinds of parametric information and pacing parameters are possible.

Brugada syndrome is a genetic disease characterized by abnormalelectrocardiogram findings and an increased risk of cardiac arrest andSCD, such as described in Braunwald, “Heart Disease—A Textbook ofCardiovascular Medicine,” p. 904 (8^(th) ed. 2008), the disclosure ofwhich is incorporated by reference. FIGS. 2 and 3 are graphsrespectively showing, by way of example, 12-lead electrocardiograms 40,50 for patients exhibiting Brugada syndrome. The syndrome is primarilycharacterized by an electrocardiogram 40, 50, or similartemporally-captured cardiac cycle physiology, that exhibits an STsegment elevation in the anterior precordial (V1, V2, V3) leads with QRScomplexes exhibiting an image of right bundle branch block in the rightprecordial leads and an elevation at the J point, which are respectivelyindicated by boxes 41, 51. In general, the electrocardiogram pattern canbe of three types, Type 1 with coved-type ST segment, Type 2 withsaddleback ST segment and Type 3 with ST segment elevated less than 1mm.

Clinically, a QRS duration in lead V2 longer than 90 msec combined withan inferolateral J wave or horizontal ST segment morphology followingthe J wave can serve as predictors of cardiac events for purposes oftreating Brugada syndrome. Referring back to FIG. 1 , Brugada syndrome,as well as other forms of related conduction problems, can be correctedby actively stimulating the region near the His bundle 16 or thepara-Hisian region 17. Two forms of pacing are used. In the first form,electrical stimulation is triggered by the direct early detection of thearrival of an activation wave front from the AV node 36 to the Hisbundle 16 or para-Hisian regions 17 of the patient's heart 11, asfurther described infra with reference to FIG. 4 . In the second form,electrical stimulation is triggered by an atrial activity, which can besensed in lieu of or in addition to His or para-Hisian events, asfurther described infra with reference to FIG. 5 .

Empirically, the electrocardiographic pattern characteristic of Brugadasyndrome can be eliminated by using an ample combination of pacing sitesand electrical stimulation amplitudes around the region near the Hisbundle 16 or in the para-Hisian region 17, on either the right atrialand right ventricular sides of the tricuspid valve 35, or in somecombination thereof. A virtual pacing electrode, when applied to theright region of the septum, allows the Brugada syndromeelectrocardiographic pattern to be normalized and the conduction andactivation abnormalities that created the pattern to be corrected. Inone embodiment, the endocardial lead 21 is guided through the tricuspidvalve 35 and the pacing electrodes 23 are placed in the para-Hisianregion 17 towards the right ventricular outflow tract, such as describedin Nakagawa et al., “Para-Hisian pacing: Useful clinical technique todifferentiate retrograde conduction between accessory atrioventricularpathways and atrioventricular nodal pathways,” Heart Rhythm, Vol. 2(6),pp. 667-72 (June 2005), the disclosure of which is incorporated byreference. In a further embodiment, the pacing electrodes 23 are placedin the region near the His bundle 16 at a point near the AV septum,superior to the tricuspid valve 35, such as described in Deshmukh etal., “Permanent, Direct His-Bundle Pacing,” Circulation, Vol. 101, pp.869-977 (2000), the disclosure of which is incorporated by reference.

Empirically, these pacing locations have been found to deliver optimumstimulation therapy when using an implanted endocardial pacing lead 21or, in a further embodiment, when using an transiently-introducedelectrophysiology catheter (not shown). The pulse generator 33 deliversa ventricular pacing output of at least two single-phase superimposedwaveforms of opposite polarity with respect to an indifferent(reference) electrode (not shown). The indifferent electrode could belocated as a third electrode in a tripolar lead, an exposed metallicsurface on the implantable CRM device's housing 28, an electrodeconnected to the implantable CRM device 19 proper, or other type ofreference voltage lead. A pulse generator and single-phase superimposedwaveforms of opposite polarity as used to bypass a conduction defectcausing an asynchronous contraction of the heart, such as described inU.S. Patent App. Pub. No. 2012/0053651, the disclosure of which isincorporated by reference, could be used as the implantable CRM device19.

The stimulation of either the region near the His bundle 16 or thepara-Hisian region 17 achieves two simultaneous ends. Three pacing modesare available, (a) dedicated DDD pacing (always ON) with a short AVinterval, (b) on-demand according to QRS width (the latter parameter canbe automatically triggered when QRS is wider than 100 msec), and (c)on-demand according to QRS width, manually compared with an averagingtemplate. There is a programmable pacing duration, whose window is alsoprogrammable from three to ten beats. The modes enable the QRS width tobe analyzed and the proper type of pacing provided, as further describedinfra with reference to FIG. 10 .

In a further embodiment, as Brugada syndrome is not present at alltimes, but instead appears and disappears as the conditions of thepatient change, the presence of the Brugada syndromeelectrocardiographic pattern can be sensed in an algorithmic way thatenables stimulation delivery only when necessary, after an appropriateAV interval; ventricular stimulation is triggered upon the sensing ofthe atrial depolarization followed by a waiting period that constitutesthe longest practicable interval that avoids bringing back the Brugadasyndrome electrocardiographic pattern.

The twofold aim of detecting the presence of Brugada syndrome andbypassing the syndrome's defects can be provided by delivering cardiacepisode-focused stimuli in the region near the His bundle 16 orpara-Hisian region 17. FIG. 4 is a flow diagram showing a method 60 fortreating Brugada syndrome through triggered pacing in accordance withone embodiment. The method 60 provides an algorithm for initiation ofthe pacing device, informing the physician of incorrect lead position,as appropriate, optimizing the pacing voltage, and deciding on whetherto continue the ventricular stimulation upon the presence of Brugadasyndrome physiology. The method 60 is operable on an implantable CRMdevice 19 under programmatic control, such as program code executable asa series of process or method modules or steps by the device's controlcircuitry, as described supra with reference to FIG. 1 .

In a further embodiment, in addition to providing pacing through thepacing electrodes 23 in the region near the His bundle 16 or para-Hisianregion 17, the implantable CRM device 19 can also wirelessly communicatewith an external electrocardiographic system, as further described infrawith reference to FIG. 11 , which can sense whether the physiologyindicative of the presence of Brugada syndrome is exhibited in thepatient's electrocardiogram. By collaborating with the externalelectrocardiographic system, energy consumption of the implantable CRMdevice 19 can be minimized by limiting the amount of ventricular pacingdelivered to the patient 10. The external electrocardiographic systemhelps the implantable CRM device 19 to avoid situations of creating apropagation wave front with inferior hemodynamic and functional efficacyin comparison to a normal propagation wave front, for instance, due toless than optimum lead positioning. In a still further embodiment, themethod 60 is operable on a transiently-introduced electrophysiologycatheter, in conjunction with an external pulse generator, such as usedto induce ventricular arrhythmias during EPS.

As an initial step, the patient's physiology is monitored to detect thepresence of Brugada syndrome (step 61). Detection can be performed byfirst sensing cardiac physiology through the sensing amplifiers 34 andthen providing the physiology to the external electrocardiographicsystem, as further described infra with reference to FIG. 11 , whichalgorithmically identifies physiology indicative of a presence ofBrugada syndrome in the patient 10. Alternatively, the detection can beperformed by the sensing amplifiers 34 and the control circuitry of theimplantable CRM device 19. If the syndrome is not present (step 62), nofurther action need be undertaken and, at later points in time, thepresence of Brugada syndrome is again repeatedly detected (step 61).

Upon a finding of the presence of Brugada syndrome in the patient 10(step 62), the patient's physiology is monitored to detect an event,specifically, propagation of an activation wave front proceeding fromthe AV node 36 of the patient's heart, either in region near the Hisbundle 16 or para-Hisian region 17 (step 63), as applicable. Thedetection can be performed by the sensing amplifiers 34 and the controlcircuitry of the implantable CRM device 19. If present (step 64),electrical stimulation therapy is delivered from the pulse generatoroutput circuitry 33 (step 65), which initiates pacing at an AV delaytriggered by atrial event sensing in the region near the His bundle 16or para-Hisian region 17, or 50 msec, whichever is lower, at a pacingamplitude of about 1.2 times threshold. If detection is being performedusing a transiently-introduced electrophysiology catheter, the samecatheter can also be used to stimulate the region. Pacing is timed to bedelivered substantially coincident to the arrival of the atrial event tothe His bundle 16 or para-Hisian region 17. A few microseconds delay canoccur between the arrival of the activation wave front and theinitiation of delivery of electrical stimulation to the region. However,from the standpoint of cardiac myocytes, the delay is de minimus and theelectrical stimulation is received simultaneously as part of theactivation wave front timed to the waveform of the atrial activation.

Pacing continues for a predetermined period of time. The pacing will bemaintained for 80 to 99% of the time, as physician-programmable due toits patient dependence, to enable for windows of time with no pacing, toverify if the pattern remains in the absence of pacing or that thesyndrome has satisfactorily resolved due to a favorable change in thesubstrate of the patient's heart. Pacing is continued for a therapyinterval that the health care personnel adjusts to the actual clinicalsubstrate of the patient being treated. In the rare case of a patient inwhich the Brugada syndrome resolves in a spontaneous manner, the healthcare personnel may program a long interval, whereas a short interval maybe more appropriate for a patient in which Brugada syndromemanifestations tend to appear for only brief periods of time.

During pacing, the patient's physiology is periodically monitored todetect the presence of Brugada syndrome (step 66), in the same mannerdescribed supra, which also confirms that the pacing amplitude of 1.2times threshold is sufficient to suppress the Brugada syndromemanifestations. If the syndrome is still present (step 67), the pacingamplitude is increased (step 70) until a programmable maximum amplitudeof 15 to 30 volts is reached, in which case the physician is advised toreview the position of the lead. Thus, if the maximum allowable pacingamplitude has been reached (step 71), a problem likely exists and achange in ventricular pacing lead position is indicated (step 72), afterwhich pacing stops (step 69) and the method ends.

Otherwise, if the syndrome is not present, yet the predetermined periodof time for pacing has not yet expired (step 68), the patient'sphysiology is again monitored to detect the presence of Brugada syndrome(step 66), as described supra. However, if the predetermined period oftime for pacing has expired (step 68), pacing is stopped (step 69) andthe method ends.

The foregoing method relied on the direct early detection of the arrivalof the activation wave front to the region near the His bundle 16 orpara-Hisian region 17. Alternatively, atrial activity can be sensed inlieu of or in addition to His or para-Hisian events. FIG. 5 is a flowdiagram showing a method 80 for treating Brugada syndrome throughoptimized atrioventricular nodal pacing in accordance with a furtherembodiment. The method 80 provides an algorithm for initiation of thepacing device, informing the physician of incorrect lead position, asappropriate, optimizing AV delay and pacing voltage, and deciding onwhether to continue the ventricular stimulation upon the presence ofBrugada syndrome physiology. The method 80 is operable on an implantableCRM device 19 under programmatic control, in wireless communication withan external electrocardiographic system, or on a transiently-introducedelectrophysiology catheter, in conjunction with an external pulsegenerator, as described supra.

Parts of the method are the same as performed for the direct earlyactivation wave front detection method. Thus, as an initial step, thepatient's physiology is monitored to detect the presence of Brugadasyndrome (step 81). Detection can be performed by first sensing cardiacphysiology through the sensing amplifiers 34 and then providing thephysiology to the external electrocardiographic system, whichalgorithmically identifies physiology indicative of a presence ofBrugada syndrome in the patient 10. Alternatively, the detection can beperformed by the sensing amplifiers 34 and the control circuitry of theimplantable CRM device 19. If the syndrome is not present (step 82), nofurther action need be undertaken and, at later points in time, thepresence of Brugada syndrome is again repeatedly detected (step 81).

Upon a finding of the presence of Brugada syndrome in the patient 10(step 82), the patient's physiology is monitored to detect an atrialactivation event (step 83). The detection can be performed by thesensing amplifiers 34 and the control circuitry of the implantable CRMdevice 19. If an atrial activation event is detected (step 84),electrical stimulation therapy is delivered from the pulse generatoroutput circuitry 33 (step 85), which initiates pacing at an AV delaytriggered by the atrial activity sensing; atrial pacing, where thepatient 10 requires atrial pacing, that is equal to 50% of the previousinterval between atrial and ventricular sensing; or 50 msec, whicheveris lower, at a pacing amplitude of about 1.2 times threshold. Pacingcontinues for a predetermined period of time.

During pacing, the patient's physiology is periodically monitored todetect the presence of Brugada syndrome (step 86), in the same mannerdescribed supra, which also confirms that the pacing amplitude of 1.2times threshold is sufficient to suppress the Brugada syndromemanifestations. If the syndrome is still present (step 87), the pacingamplitude is increased (step 95) until a programmable maximum amplitudeof 15 to 30 volts is reached, in which case the physician is advised toreview the position of the lead. Thus, if the maximum allowable pacingamplitude has been reached (step 96), a problem likely exists and achange in ventricular pacing lead position is indicated (step 97), afterwhich pacing stops (step 94) and the method ends.

Once the lowest voltage at which the manifestations of Brugada syndromeare removed has been found, the atrioventricular AV delay is increased.The delay between atrial activation events is optimized to reflect thelongest AV delay permitted without affecting the reappearance of theBrugada syndrome manifestations. The AV delay is fine-tuned bycontinually monitoring the patient's physiology to detect the presenceof Brugada syndrome. Otherwise, if the syndrome is not present (step87), the AV delay is increased (step 88). The AV delay is slowlyincreased in steps of one to 20 msecs, with 5 msecs being preferable,until the Brugada syndrome electrocardiographic pattern reappears.Following a period of pacing, the patient's physiology is once againmonitored to detect the presence of Brugada syndrome (step 89), in thesame manner described supra. If the syndrome is no longer present (step90) and the maximum AV delay has not yet been reached (step 91), the AVdelay is again increased (step 88). However, if the maximum AV delay hasbeen reached without affecting the reappearance of the Brugada syndromemanifestations (step 91), the AV delay is shorted back to the previousAV delay (step 92) and pacing is continued for a therapy interval thatthe health care personnel adjusts to the actual clinical substrate ofthe patient 10 being treated. Using the longest AV delay that stillremoves the undesired effects of Brugada syndrome ensures that theoptimal preload will be minimally affected by the stimulation, thusmaintaining near normal hemodynamics in the heart. The pacing will bemaintained for 80 to 99% of the time, as physician-programmable due toits patient dependence, to enable for windows of time with no pacing, toverify if the pattern remains in the absence of pacing or that thesyndrome has satisfactorily resolved due to a favorable change in thesubstrate of the patient's heart.

If the predetermined period of time for pacing has expired (step 93),pacing is stopped (step 94) and the method ends.

As battery technology improves and processing power becomes lessexpensive in terms of cost and battery life, the algorithm to detect thepresence of the Brugada syndrome electrocardiographic pattern could beinternally implemented as part of the control circuitry of theimplantable CRM device 19. FIG. 6 is a flow diagram showing a method 100for selecting an algorithm for detecting Brugada syndrome for use inconjunction with the methods of FIGS. 4 and 5 . To select an appropriateBrugada syndrome detection algorithm, the patient's physiology wouldfirst be evaluated (step 101), then compared to against a set of storedpredefined algorithms (step 102). A new algorithm specific to thepatient could be created from the physiology (step 105) if desired (step104). Depending upon the cost tradeoffs of development, production,maintenance, regulatory compliance, and other factors at the time ofproduction, an individualized algorithm could be created that maps foreach patient the changes in the intracardiac electrocardiographicpatterns that are detected with the implanted sensing electrodes 24, 26to the presence or absence of the Brugada syndrome electrocardiographicpattern as registered by an external electrocardiographic system.Otherwise, a best matching detection algorithm could be chosen for thepatient 10 (step 105), whether a standard “one size fits all” algorithm,an algorithm selected from a set of generic algorithms to coverdifferent classes of patients, or other suitable form of detectionalgorithm.

Once selected, the detection algorithm can be provided to theimplantable CRM device 19 (step 106), or to an externalelectrocardiographic system, external sensor, or programmer, ifdetection of Brugada syndrome is being performed transiently, such asduring EPS. During use, the device will match the electrographicdifferences detected by the sensing electrodes 24, 26 with the Brugadasyndrome electrocardiographic pattern specified in the detectionalgorithm for the patient 10.

In a still further embodiment, an individualized algorithm could bedeveloped directly from the patient's physiology and automaticallyuploaded into the device used for Brugada syndrome detection. Thisapproach would have the advantage of not limiting the set of parametersthat would need to be adjusted to ensure an univocal match between theBrugada syndrome electrocardiographic pattern, as detected by anexternal ECG system, and by the internal algorithm in the implantableCRM device 19, or external device, as applicable. In addition, advancesin signal processing would enable continual creation of improveddetection algorithms, even after the device has already been implantedin the patient 10. Still other ways to formulate Brugada syndromedetection algorithms and to equip an implantable CRM device 19 orexternal device are possible.

The precise mechanism by which Brugada syndrome causes arrhythmias isunknown, but has been theorized to be due to transmural depolarizationdispersion or transepicardial repolarization dispersion, which can leadto reentrant VTs in Phase 2. Brugada syndrome is characterized byalterations in several ion channels, and, in particular, changes in thesodium ion channel with overexpression of cardiac transient outwardpotassium current. These changes are mainly expressed in the epicardiumwith higher endo-to-epi repolarization gradients that facilitate there-entry mechanisms in polymorphic cells.

The cardiac stimulation delivered by the implantable CRM device 19, orexternal device, as applicable, used in treating Brugada syndromecompensates for electrical shifts in the balance of thevoltage-dependent sodium, potassium and, eventually, calcium ionchannels by applying a relatively intense electrical field. Thiselectrical field facilitates normalizing those channelopathies, afterwhich the electrocardiographic signs of Brugada syndrome disappear,along with the specter of its sudden death manifestation. To enable thefollowing physician or health care provider to verify the disappearanceof the electrocardiographic manifestations of Brugada syndrome, thecardiac stimulation must not be allowed to produce alterations in theelectrocardiogram that could mask the signs typical of Brugada syndrome,for instance, the left ventricular bundle block image of rightventricular apical pacing. The normal conduction through theHis-Purkinje system produces a fast, sequential, synchronousdepolarization of the myocardial fibers, making the ventricularcontraction more efficient. Consequently, the region near the His bundle16 and the para-Hisian region 17 are ideal pacing sites for maintaininga normal activation pattern and enabling the verification of thedisappearance of the Brugada syndrome electrocardiographic pattern.

A foregoing approach allows the generation of an activation wave frontwith near-normal ventricular depolarization and narrow QRS complexes inpatients that already exhibit narrow basal QRS complexes. This type ofactivation wave front is well suited to eliminating the typicalelectrocardiographic signs of Brugada syndrome. Near-physiologicstimulation is delivered substantially simultaneously to atrialactivation by using a “virtual electrode” that allows the creation of astimulation field far stronger than a conventional electrode, which cancorrect the depolarization and conduction abnormalities present inBrugada syndrome. Moreover, this stronger stimulation field entrainsareas that are farther away from the actual pacing site and can therebyovercome conduction disturbances. Thus, the use of this “virtualelectrode” facilitates locating the pacing electrodes 23 in a location,specifically, the region near the His bundle 16 or para-Hisian region17, that allows the health care operator to correct and effectivelyeliminate the Brugada syndrome electrocardiographic pattern, therebyobviating the need to perform complex electrophysiologic mappingprocedures to define the stimulation site.

As delivered through the pacing electrodes 23, the high-energystimulation at septal level modifies the electrocardiographic pattern inleads V1, V2, V3 through a “homogenizer effect” over the transmuralepicardium/endocardium voltage gradient by acting on the involvedvoltage-dependent ionic channels and restoring an adequateepicardium/endocardium voltage ratio. There is also a homogenizingeffect on the epicardium/endocardium repolarization dispersion, as wellas in the intraepicardiac dispersion. The efficacy of the stimulationherein provided is theorized to be based on the fundamentallyvoltage-dependence, and consequently the “virtual electrode effect” atseptum level, of the ionic sodium and potassium cellular channels. Thestimulation could be modifying the altered charges in the epicardiumarea of the right ventricular outflow tract, which is close to thepacing sites used, that is, the region near the His bundle 16 and thepara-Hisian region 17 of the heart 11. Alternatively, the “virtualelectrode effect” may simply be due to the increase in the initialdepolarization voltage, correcting and activating a small number (aboutone percent) of “slow” sodium channels, consequently eliminating theoverexpression of the potassium current (Ito) evident in theelectrocardiogram by elimination of the Brugada syndrome-typical patternin leads V1, V2, V3. Last, a “tsunami effect” that modifies all thecurrents, including those of sodium, potassium and calcium in itsvarious forms, may be triggered through the pacing and thus preventingreentry in Phase 2.

The waveforms and amplitudes used in the electrical stimulationdelivered through the foregoing methods described supra with referenceto FIGS. 4 and 5 , by the implantable CRM device 19, or external device,as applicable, has been verified through clinical experiments to bypassthe activation and conduction problems underlying the Brugada syndromeelectrocardiographic pattern. FIGS. 7A-B, 8A-B and 9A-B are graphsrespectively showing, by way of example, 12-lead electrocardiograms forpatients exhibiting Brugada syndrome following treatment through themethods of FIGS. 4 and 5 . Referring first to FIGS. 7A-B, the patientexhibiting manifestations of Brugada syndrome, as described supra withreference to FIG. 1 , has undergone pacing in the para-Hsian region 17.Following therapy, several differences in cardiac profile can be noted,including a change of axis and elimination of left anterior fascicularblock (box 1), a change in pattern in lead augmented vector right (aVR)(box 2), a disappearance of Brugada syndrome pattern in leads V1 and V2(box 3), and a post-pacing reappearance of the syndrome'smanifestations. No changes in J point or T wave in lead V3 areexhibited.

Referring next to FIGS. 8A-B, the patient exhibiting manifestations ofBrugada syndrome, as described supra with reference to FIG. 2 , hasundergone pacing in the septal para-Hsian region 17. Following therapy,a change in pattern in aVR and a disappearance of Brugada syndromepattern in leads V1 and V2 can be observed.

Finally, referring to FIGS. 9A-B, the same patient has again undergonepacing in the septal para-Hsian region 17. Following therapy, as before,a change in pattern in aVR (box 1) and a disappearance of Brugadasyndrome pattern in leads V1 and V2 can be observed, as well as apartial reapparition (boxes 2-3) after a few beats and morphology thesame as presented pre-pacing. No changes in J point or T wave in lead V3are exhibited (box 4).

The three pacing modes enable the QRS width to be analyzed and theproper type of pacing provided. FIG. 10 is a flow diagram showing amethod 100 for sensing QRS width for use in conjunction with the methodsof FIGS. 4 and 5 . The implantable CRM device 19 has at least threeprogrammable parameters for pacing, which are para-Hisian, apex, or bothpara-Hisian and apex, and at least two values that reflect changes inthe QRS width, which are coil-to-coil and ring-to-distal coil(programmable).

First, if Brugada syndrome QRS width sensing is not enabled (step 101),sensing and pacing are provided as for a DDD CRT device (step 102).Otherwise, if Brugada syndrome QRS width sensing is enabled (step 101)and the device is set to automatic mode (step 104), the QRS width ismeasured (step 104). If the QRS width is less than 100 msec (step 105),pacing for a short AV interval is provided (step 107). Otherwise, if theQRS width is equal to or greater than 100 msec (step 105), the QRSduration is sensed (step 106). If the device is not set to automaticmode (step 104), a manual adjustment template is used (step 108). If aBrugada syndrome pattern is apparent (step 109), pacing for a short AVinterval is provided (step 107). Otherwise, if a Brugada syndromepattern is not apparent (step 109), the QRS width is sensed (step 110).

The pacing therapy can be delivered wholly in situ via an implantableCRM device 19 that performs sensing, detection algorithm analysis andpacing. Alternatively, the implantable CRM device 19 could be remotelycoupled to an external electrocardiographic system that wouldcollaboratively perform select aspects of the end-to-end treatmentregime. FIG. 11 is a functional block diagram showing acomputer-implemented system 130 for treating Brugada syndrome, inaccordance with a further embodiment. The system 130 includes anexternal electrocardiograph machine 133, conventional externalprogrammer 131 and an external computer 136. Other components are alsopossible.

The external electrocardiograph machine 133, or similar device, cancapture an electrocardiogram of the patient 10 at different points ofthe pacing therapy, as described supra, which can be used to identifyphysiology indicative of a presence of Brugada syndrome in the patient.The external electrocardiograph machine 133 can be a conventionalelectrocardiograph machine that uses a set of twelve precordial leads134 (shown as a single across-the-chest “strap” for the sake ofsimplicity) to record an electrocardiogram. In a further embodiment, theexternal electrocardiograph machine 133 relies on the implantable CRMdevice 19 to temporally capture cardiac cycle physiology, which is theninterpreted by either the external electrocardiograph machine 133 or anexternal computer 136, as described infra, into an electrocardiogram orsimilar form of temporal mapping of the cardiac cycle physiology.

The conventional external programmer 131, or similar device, canremotely communicate with the implantable CRM device 19 using aninductive (or wireless) communications channel to enable remoteparametric programming of and stored physiologic data offload from thedevice. The programmer 131 includes a physically-connected programmerwand 132, which is placed by health care personnel over the patient'spectoral region above the implantable CRM device 19 to initiate andcarry out programmer-to-CRM device communications.

The external computer 136, or similar device, can be wirelessly (orinductively) interfaced to the implantable CRM device 12. The externalcomputer 136 receives cardiac cycle physiology, as recorded by theimplantable CRM device 12 via the wireless communications channel.Alternatively, cardiac cycle physiology or, equivalently,electrocardiograms, can be retrieved by the external computer 136 fromthe external electrocardiograph machine 133, or other source. Theexternal computer 136 algorithmically identifies physiology indicativeof a presence of Brugada syndrome in the patient 10. In addition, theexternal computer 136 can create an individualized algorithm for eachpatient 10 that maps the changes in the intracardiacelectrocardiographic patterns that are detected with the implantedsensing electrodes 24, 26 to the presence or absence of the Brugadasyndrome electrocardiographic pattern as registered in the cardiac cyclephysiology or electrocardiograms.

Finally, the system 130 can include a centralized server 137 coupled toa database 138 within which patient data, such as the electrocardiogramsand algorithms, are stored. The external electrocardiograph machine 133,external programmer 131, and the external computer 136 can interfacewith the centralized server 137 through a network 135, such as apublicly available wide area network, including the Internet. Otherforms of remote server interfacing are possible.

In a yet further embodiment, the system 130 can be adapted for use inEPS, whereby a transiently-introduced electrophysiology catheter (notshown) serves the functions of the implantable CRM device 19, which caneither be temporarily rendered inoperable or be absent from the patient10 altogether.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope.

What is claimed is:
 1. A system for Brugada syndrome presence-basedelectrical therapeutic stimulation delivery comprising: a cardiac pacingdevice comprising a pulse generator and a pair of pacing electrodeselectrically coupled to the pulse generator via an endocardial lead andpositioned in one of a region near the His bundle and a para-Hisianregion of a patient's heart, the pulse generator configured to deliverelectrical therapeutic stimulation through the pair of pacing electrodessubstantially coincident to propagation of an activation wave frontproceeding from the atrioventricular node of the patient's heart; and adiagnostic module operatively coupled to the pulse generator andconfigured to sense via one or more sensing electrodes physiologyassociated with a presence of Brugada syndrome in the patient, thediagnostic module further configured to control the pulse generator indelivering the electrical therapeutic stimulation in response to thepresence of the Brugada syndrome, wherein the physiology associated withthe presence of Brugada syndrome comprises a QRS duration in a lead V2longer than 90 msec and one of an inferolateral J wave and a horizontalST segment morphology following a J wave.
 2. A system according to claim1, further comprising: a control circuitry in control of the pulsegenerator.
 3. A system according to claim 2, wherein the controlcircuitry comprises a transducer configured to interface with anexternal programmer via inductive signal conversion.
 4. A systemaccording to claim 3, wherein the external programmer performs remoteparametric programming of the cardiac pacing device and receivesphysiologic data offload via the transducer.
 5. A system according toclaim 4, wherein the external programmer comprises a wand configured tointerface with the transducer when placed over a pectoral region of thepatient.
 6. A system according to claim 1, wherein the diagnostic moduleis at least one of wirelessly and inductively coupled to the cardiacpacing device.
 7. A system according to claim 1, wherein the diagnosticmodule is at least one of wirelessly and inductively coupled to thecardiac pacing device.
 8. A system according to claim 1, wherein thecardiac pacing device comprises the one or more sensing electrodes andwherein the electrical therapeutic stimulation is further deliveredbased on intracardiac electrocardiographic patterns that are detectedusing the one or more sensing electrodes.
 9. A system according to claim8, further comprising: an external computer configured to receive thephysiology sensed by the diagnostic module, to develop an individualizedalgorithm for application of the electrical therapeutic stimulationalgorithm for the patient based on the sensed physiology, and to providethe algorithm to the cardiac pacing device, wherein the cardiac pacingdevice uses the algorithm to analyze the intracardiacelectrocardiographic patterns.
 10. A system according to claim 1,wherein at least one sensing electrode is comprised in at least one ofthe pacing electrodes.
 11. A system according to claim 1, furthercomprising: at least one sensing amplifier comprised in the diagnosticmodule and configured to sense the physiology under a control of controlcircuitry of the cardiac pacing device; and the control circuitryconfigured to identify the physiology as indicative of the presence ofBrugada system in the patient.
 12. A system according to claim 1,further comprising: the diagnostic module further configured during thedelivery of the therapeutic electrical stimulation to sense via the atleast one sensing electrode physiology indicative of a reoccurrence ofBrugada syndrome in the patient and to change one or more parameters ofthe therapeutic electrical stimulation.
 13. A cardiac rhythm managementsystem for treating Brugada syndrome, comprising: an endocardial leadcomprising a pair of pacing electrodes and at least one sensingelectrode both on a distal end that has been positioned in one of aregion near the His bundle and a para-Hisian region of a patient'sheart; and a cardiac rhythm management device comprised in a sealedhousing and further comprising: a sensing amplifier electrically coupledto the endocardial lead and configured to detect through the at leastone sensing electrode propagation of an activation wave front proceedingfrom an atrioventricular node; a pulse generator electrically coupled tothe endocardial lead and configured to deliver electrical therapeuticstimulation under programmed parametric control, the pulse generatorfurther configured to deliver the electrical therapeutic stimulationthrough the pair of pacing electrodes substantially coincident to theactivation wave front as detected by the sensing amplifier; and adiagnostic module operatively coupled to the pulse generator and thesensing amplifier and configured to sense via the at least one sensingelectrode physiology associated with a presence of Brugada syndrome inthe patient, the diagnostic module further configured to control thepulse generator in delivering the electrical therapeutic stimulation inresponse to the presence of Brugada syndrome, wherein the physiologyassociated with the presence of Brugada syndrome comprises a QRSduration in a lead V2 longer than 90 msec and one of an inferolateral Jwave and a horizontal ST segment morphology following a J wave.
 14. Asystem according to claim 13, further comprising: a control circuitry incontrol of the pulse generator.
 15. A system according to claim 14,wherein the control circuitry comprises a transducer configured tointerface with an external programmer via inductive signal conversion.16. A system according to claim 15, wherein the external programmerperforms remote parametric programming of the cardiac rhythm managementdevice and receives the physiology via the transducer.
 17. A systemaccording to claim 16, further comprising a memory configured to storethe physiology and from which the transducer obtains the physiology forproviding to the external programmer.
 18. A system according to claim13, further comprising: an external electrocardiographic systemconfigured to receive the sensed physiology and to identify thephysiology as indicative of the presence of Brugada system in thepatient.
 19. A system according to claim 17, wherein the externalelectrocardiographic system is an electrocardiograph machine that uses aset of twelve precordial leads.
 20. A catheter-based cardiac rhythmmanagement system for treating Brugada syndrome, comprising: anelectrophysiology catheter configured to be transiently-introduced intothe heart of a patient and comprising a plurality of electrodes on adistal end; a sensing amplifier electrically coupled to theelectrophysiology catheter and configured to detect through theelectrodes propagation of an activation wave front proceeding from anatrioventricular node; and a pulse generator electrically coupled to theelectrophysiology catheter and configured to deliver electricaltherapeutic stimulation under programmed parametric control through theelectrodes via the electrophysiology catheter when distally positionedin one of a region near the His bundle and a para-Hisian region of apatient's heart, the pulse generator further configured to deliverelectrical therapeutic stimulation through the electrodes substantiallycoincident to the activation wave front as detected by the sensingamplifier; and a diagnostic module operatively coupled to the pulsegenerator and the sensing amplifier and configured to sense via at leastone of the electrodes physiology associated with a presence of Brugadasyndrome in the patient, the diagnostic module further configured tocontrol the pulse generator in delivering the electrical therapeuticstimulation in response to the presence of Brugada syndrome, wherein thephysiology associated with the presence of Brugada syndrome comprises aQRS duration in a lead V2 longer than 90 msec and one of aninferolateral J wave and a horizontal ST segment morphology following aJ wave.